VARIABLE GENE-EXPRESSION WITHIN HUMAN TYROSINEMIA TYPE-1 LIVER MAY REFLECT REGION-SPECIFIC DYSPLASIA

Patients with hereditary tyrosinemia type 1 have a deficiency of fumar ylacetoacetate hydrolase (FAH) and develop progressive hepatocellular dysfunction with a high risk of malignant transformation, Serum alpha- fetoprotein levels are frequently elevated in these patients; therefor e, this commonly used marker of tumorigenesis is inadequate, To date, no literature exists describing the hepatic gene alterations in patien ts with this disease, We analyzed the expression of a panel of prolife ration-associated and liver-specific genes in the liver of a 33-month- old girl at the time of orthotopic liver transplantation, This study p rovides information that may be useful in developing markers for malig nancy and understanding the pathogenesis of this disease, Gene express ion patterns of two regenerating nodules and total liver from the pati ent with FAB deficiency were compared with control donor liver, Liver- specific and growth-induced genes with altered expression in the tyros inemic liver included several functional classes: structural proteins (actin, thrombospondin), transcription factors (c-fos, egr-1, C/EBP al pha), liver-specific enzymes (glucose-6-phosphatase [G6Pase]), and sec reted factors (insulinlike growth factor binding protein 1 [IGFBP-1]). Isolated macronodules demonstrated varied patterns of expression, sug gesting that they do not form a homogeneous cellular environment, In t he tyrosinemic liver, IGFBP-1 messenger RNA expression was high and G6 Pase messenger RNA was not detectable, Although G6Pase and IGFBP-1 are coexpressed in regenerating liver, immunohistochemistry in the tyrosi nemic liver demonstrated a mutually exclusive distribution for the two proteins in a tissue section with features of dysplasia, We propose t hat cells in these areas may have an aberrant transcription factor and growth factor ''milieu'' that leads to altered gene and protein expre ssion, These molecular alterations are reflected in dysplastic histolo gical changes and may ultimately predispose to the development of mali gnancy.